JVRS‐100 (lipid‐DNA complexes) is a unique and promising adjuvant for vaccine applications that require high levels of antibody and T‐cell immunity. The JVRS‐100 adjuvant was mixed with a split influenza vaccine (Fluzone®‐sanofi pasteur) and administered parenterally to mice, rabbits and non‐human primates. Vaccination with JVRS‐100‐Fluzone® resulted in a significant increase in total IgG, IgG1 and IgG2a influenza antibodies. Further hemagglutination inhibiting (HAI) antibody were higher compared with Fluzone® alone. Administration of decreasing amounts of Fluzone® mixed with JVRS‐100 resulted in a ∼50‐fold dose‐sparing effect based on HAI titer. In vitro stimulation of splenocytes from JVRS‐100‐Fluzone® vaccinated mice with Fluzone® demonstrated increased antigen‐specific T cell responses (IFN‐gamma production) compared with Fluzone® alone. Splenocytes from JVRS‐100‐Fluzone® vaccinated mice responded to unmatched H1N1, or H3N2, and influenza B viruses, suggested induction of cross‐reactive T cell responses to conserved viral antigens. These results suggest the JVRS‐100 adjuvant enhanced immune responsiveness and reduced antigen doses needed for strong immune responses to a licensed flu vaccine. The JVRS‐100 adjuvant has also been shown to potentiate immune responses to multiple viral and bacterial antigens, and could be a broadly applicable adjuvant for human and veterinary vaccines.